Plasminogen activator inhibitor-1 is an independent prognostic factor of ovarian cancer and IMD-4482, a novel plasminogen activator inhibitor-1 inhibitor, inhibits ovarian cancer peritoneal dissemination
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Erika Nakatsuka1, Kenjiro Sawada1, Koji Nakamura1, Akihito Yoshimura1, Yasuto Kinose1, Michiko Kodama1, Kae Hashimoto1, Seiji Mabuchi1, Hiroshi Makino2, Eiichi Morii3, Yoichi Yamaguchi4, Takeshi Yanase4, Akiko Itai4, Ken-ichirou Morishige2 and Tadashi Kimura1
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
2Department of Obstetrics and Gynecology, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan
3Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
4IMMD Inc., Tokyo, Japan
Kenjiro Sawada, email: [email protected]
Keywords: ovarian cancer, PAI-1, IMD-4482, peritoneal dissemination, angiogenesis
Received: November 23, 2016 Accepted: August 06, 2017 Published: September 12, 2017
In the present study, the therapeutic potential of targeting plasminogen activator inhibitor-1 (PAI-1) in ovarian cancer was tested. Tissues samples from 154 cases of ovarian carcinoma were immunostained with anti-PAI-1 antibody, and the prognostic value was analyzed. Among the samples, 67% (104/154) showed strong PAI-1 expression; this was significantly associated with poor prognosis (progression-free survival: 20 vs. 31 months, P = 0.0033). In particular, among patients with stage II-IV serous adenocarcinoma, PAI-1 expression was an independent prognostic factor. The effect of a novel PAI-1 inhibitor, IMD-4482, on ovarian cancer cell lines was assessed and its therapeutic potential was examined using a xenograft mouse model of ovarian cancer. IMD-4482 inhibited in vitro cell adhesion to vitronectin in PAI-1-positive ovarian cancer cells, followed by the inhibition of extracellular signal-regulated kinase and focal adhesion kinase phosphorylation through dissociation of the PAI-urokinase receptor complex from integrin αVβ3. IMD-4482 caused G0/G1 cell arrest and inhibited the proliferation of PAI-1-positive ovarian cancer cells. In the xenograft model, IMD-4482 significantly inhibited peritoneal dissemination with the reduction of PAI-1 expression and the inhibition of focal adhesion kinase phosphorylation. Collectively, the functional inhibition of PAI-1 significantly inhibited ovarian cancer progression, and targeting PAI-1 may be a potential therapeutic strategy in ovarian cancer.
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